Neuroimaging studies of mid-life major depressive disorder (MDD), have revealed abnormalities of cerebral function and structure that persist beyond depressive episodes. To test hypotheses about the neurobiological basis of MDD, the systems implicated by these studies will be examined in a unique and informative sample of young adults: Subjects now age 18 to 24 previously identified in childhood as having MDD or as being at 'high risk' (HR) for developing MDD by virtue of having multiple affected relatives. These samples will be compared against healthy, low-risk' (LR) controls (who have no evidence of having first or second degree relatives with mood disorders) with respect to PET and MRI imaging measures of neurophysiology, serotoninlA receptor binding potential (BP), and neuromorphometry that proved abnormal in both the symptomatic and asymptomatic phases of mid-life MDD). Since these abnormalities involve brain structures implicated in emotional behavior by lesion analysis, electrophysiological orPET/fMRI-brain mapping studies, they appear likely to be relevant to the pathogenesis of mood disorders. It remains unclear, however, whether such abnormalities reflect developmental or acquired processes that predate the onset of depressive episodes, or whether they instead comprise sequelae of recurrent illness or treatment in MDD. The proposed project addresses this question by bringing these measures closer to the developmental period in young adults with childhood-onset MDD and by assessing their existence in subjects at high risk for MDD. Three samples will be selected: childhood-onset MDD subjects who are unmedicated and in remission, HR subjects who are psychiatrically healthy, and LR healthy controls. PET measures of serotoninlA (5-HTIA) receptor binding and glucose metabolism will be acquired using serial injection of the 5-HTJA receptor ligand, jcarbonyl-11C] WAY-100635, and 18F-fluorodeoxyglucose. MRI-based neuromorphometric assessments of the subgenual prefrontal cortex (PFC; where reduced grey matter was found in both in vivo MRI and post mortem neuropathological studies of MDD) will also be performed. We will test the hypotheses that, relative to the LR control group, both the MDD and the HR groups will have reduced 5-HT1A receptor BP in the mesiotemporal cortex and the raphe, decreased left subgenual PFC volume, increased left amygdala metabolism, and decreased dorsomedial/dorsal anterolateral PFC metabolism. In post hoc comparisons, the relationship between the PET data and plasma and salivary cortisol levels will be assessed to test the hypotheses that 5-HT1A receptor binding down-regulation in MDD is related to elevated cortisol exposure, and to explore whether HR subjects with past evidence of HPA-axis dysregulation have reduced 5-HT1A receptor BP.